Monday, November 19, 2007

The sickle cell gene's recent introgression into East Africa

This is a "Short Report" and it is indeed very short! It seems like they assume that patterns of mt-DNA and Y-chromosome diversity are not subject to forces of selection and just represent neutral "population-level forces". I wonder how safe this assumption is? Here is the basis of their test:

By typing both the haploid Y chromosome and the S gene in the same samples it should be possible to test for common demography as well as detect affinities of particular S variants observed in Sudan to other regions of Africa.

their conclusion:

Our results suggest that the sickle cell gene may have been preferentially introduced through males of migrating west African tribes (Figure 1), particularly Hausa-Fulani, and Bagara in the large migrations that began in the eighteenth century and escalated during the nineteenth and early twentieth century. The estimates of a recent figure of 1–3 generations for the introduction of the gene and associated haplotypes to eastern Sahel, is consistent with demography during the past 100 years and with a hypothesis of a recent origin of malaria as a major human infection.

"recent origin of malaria as a major human infection" - hmm...interesting!

Abstract: The Sahel that extends from the Atlantic Ocean to the Ethiopian highland is a historical reservoir of Africa's cultures and grandest populations and a known arena of ancient and recent migrations. We are interested in the issue whether such migrations were also carriers of genetic traits and whether this introgression could be associated with population genetic markers. Based on analysis of Y-chromosome haplogroups, we present evidence that the sickle gene, one of the major protective polymorphisms known in malaria, has in fact found its way only recently to the gene pool of the populations in eastern Sahel. We discuss the possible dynamics of the process and give estimates of the age of the introduction of the S allele into eastern Sahel.

2 comments:

There is a relatively new treatment for sickle cell beingproduced in Nigeria by an American company called NICOSAN®,it's proprietary name is NIPRISAN® . It was developed onthe premise of traditional Nigerian plant based medicinalpractices for the treatment of sickle cell disease.

It has been tested through phase IIb clinical trials andfound to be highly efficacious. Phase III trials have yetto be completed however it was approved for sale in Nigeriabased on phase IIb trials and toxicity studies which showedit to be safe and non-toxic.

This drug is a major advancement in the treatment of sicklecell disease unfortunately it is not available in the U.S..Although the compound has been granted orphan drug statusby the FDA and the regulatory body of the European Union,to date investigational drug applications for the approvalprocess have yet to be submitted. Getting a drug approvedin either area is extremely expensive. Until there isfunding available to proceed with the FDA and EUapplications it will be difficult for non-Nigerians toobtain the drug.

I do say difficult but it is not impossible. If you have ahematologist or hemoncologist who is willing to put fourththe effort there are special dispensations availablethrough the FDA for the importation of unapproved drugs ona compassionate use basis.

"Expanded access program (EAP). EAPs are typically designedto provide widespread access to a drug that has provenefficacy in clinical trials but is still awaiting FDAapproval. They’re similar to standard clinical trials witha specific treatment plan and certain FDA requirements, butthey have looser patient eligibility criteria. More than23,000 U.S. cancer patients enrolled in an EAP for Iressabefore it was FDA-approved, for example."

"Single patient use. This program offers an experimentaldrug to an individual patient, rather than a group. The FDAapproves these uses on a case-by-case basis. Decisions arebased on other treatments already available and informationabout the drug’s efficacy and potential toxicities."

To date I have no knowledge that anyone has sought anysingle use or expanded access from the FDA for Nicosan.Unfortunately regardless of the dissemination of thisinformation thus far no one has put forth the effort toobtain the drug for use.

If just one person would start the ball rolling with acaring and concerned medical practitioner it could open upthe drug for wide spread use by tens of thousands ofpatients across the U.S. Unfortunately thus far the generalresponse I receive is that people don't believe that theirphysician would be interested in going to this sort ofeffort nor do they themselves seem to be inclined to seekthe use of a treatment that could potentially end theircrises.

There has to be at least one physician out there who hasenough care and concern for his patients to be willing toput forth the effort necessary to obtain this medicationlegally. I urge anyone who is effected by sickle cell toapproach their physicians with this information and attemptto obtain this treatment not only for themselves but forall patients who could potentially benefit from it's use.

We already know the benefits of the treatments available inthe U.S. and the E.U.. In many cases they are onlymarginally effective or in the case of hydroxyurea causeside effects so serious that many choose not to use it astreatment. Here we have an opportunity to use a treatmentthat has been shown to be highly effective, eradicatingcrises in the majority of patients and reducing crises by50% in the most refractory cases.

Although the clinical trial group was what the casualreader might interpret as quite small it is common fordrugs which fall into the orphan drug category to use smallsample groups. Many orphan drugs have been approved basedon very small phase II and phase IIb clinical trials in theU.S. In the case of FDA fast track status, a drug may beapproved during phase II trials if the drug showssignificant advantage over current approved therapies forlife threatening illness.

Fast Track Designation is a program that, if granted, isdesigned to facilitate the development and expedite thereview of new drugs, thereby allowing the FDA to approvedrugs used to treat a serious condition or alife-threatening disease with less safety data followingthe conclusion of phase II studies, rather than phase III,the normal practice.

The main criterion for a Fast Track Designated drug is thepotential to treat a life-threatening illness or fill amajor unmet medical need. Fast Track may be submitted withthe IND or at any time during the clinical development ofthe drug. The Fast Track designation may allow a company'sapplication to follow Priority Review, Standard Review, ora Rolling Review of the application.

http://www.fda.gov/CbER/gdlns/fsttrk.pdf

Nicosan by Western standards is an extremely inexpensivedrug. It is available in Nigeria without prescription at$23/month for adults and child doses at $18/month.

Here is a link to the company and product website.

http://xechemnigeria.com/products.htm

I sincerely hope that you find this information helpful. Iwould encourage you to to forward and post this informationto any person, blog or website where persons effected bysickle cell anemia can have access to this information.

Evaluation of Niprisan (Herbal Medicine) for the Management of Sickle Cell Anaemia

Charles Wambebe and Hadiza Khamofu, International Biomedical Research in Africa, Abuja, Nigeria, wambebe@yahoo.com, Joseph Okogun, Nathan Nasipuri and Karynius Gamaniel, National Institute for Pharmaceutical Research and Development, Abuja, Nigeria.

About 70% of all sickle cell anemia (SCA) subjects reside in Africa, estimated at over 12 million. The prevalence of SCA is estimated at over 2% while infant mortality is about 8% and survival rate of SCA babies in rural areas by five years of age is about 20%. These statistics indicate that SCA is probably the most neglected (and sometimes forgotten by health authorities) serious public health disorder with serious mortality and morbidity rates in Africa. The objective was to undertake pre-clinical and clinical assessments of a herbal extract vis-à-vis management of sickle cell anemia using Good Laboratory Practice and Good Clinical Practice principles respectively. In Africa, there is no standard treatment for sickle cell anemia, only palliative management is generally available. In view of this situation, most SCA subjects use herbal medicines. NIPRISAN is a standardized extract from four medicinal/food plants: Piper guineenses seeds, Pterocarpus osun stem, Eugenia caryophyllum fruit and Sorghum bicolor leaves. Short term toxicity study indicated that NIPRISAN was safe in laboratory animals. Bio-activity guided fractionation show that vanillin and aromatic aldehydes may be the bioactive moieties. NIPRISAN reversed sickled red blood cells and protected them from being sickled when exposed to low oxygen tension. NIPRISAN dose- dependently delayed polymer formation of haemoglobin S. NIPRISAN induced 85% increased solubility of deoxy haemoglobin S. The in vivo efficacy study was undertaken at Children Hospital of Philadelphia, USA. Histological examination of lungs of control Tg transgenic mice carrying human sickle haemoglobin showed entrapment of massive numbers of sickled cells in alveolar capillaries. NIPRISAN significantly cleared the lungs of sickled cells. Furthermore, NIPRISAN induced profound effect on the survival time of Tg mice under hypoxic conditions (p<0.0001). The phase II clinical data indicated that all the subjects benefited from NIPRISAN with no serious adverse effect. About 80% of the subjects did not experience any crisis during the study (12 months). The subjects experienced significant reduction in hospital admission while attendance at school profoundly increased. Furthermore, there was no evidence of kidney or liver damage. NIPRISAN has been patented, licensed to an American company, registered and being manufactured at Abuja for global market.